The goal of this proposal is to develop and evaluate a novel influenza vaccine that incorporates conserved internal components of influenza virus such as the nucleoprotein (NP) with a potential to induce protective immunity against divergent and potentially pandemic influenza strains. The hypothesis of this proposal is that the nucleoprotein (NP) of influenza virus linked to an immunostimulatory oligonucleotide (ISS) will induce strong Th1 and CTL responses that will cross-react with widely divergent influenza A strains due to the conserved nature of the nucleoprotein molecule. The immune response induced by the NP-ISS linked material may additionally provide cross-help to enhance the response to other viral antigens such as HA, when co-administered in a vaccine, or when subsequently encountered in association with NP during viral infection. The Specific Aims of the program are: [unreadable] 1. Produce a nucleoprotein immunostimulatory oligonucleotide conjugate (NP-ISS) and demonstrate potent induction of Th1 and CTL responses by the NP-ISS vaccine in naive and previously infected mice. [unreadable] 2. Evaluate the protective immunity provided by the NP-ISS vaccine, or NP-ISS mixed with monovalent inactivated whole virus vaccine against homologous and divergent influenza strains in mice. [unreadable] 3. Test the immunogenicity of NP-ISS, and NP-ISS combined with standard split vaccine in primates compared to standard split vaccine alone. [unreadable] 4. Perform GMP scale-up manufacture and IND-enabling toxicology with NP-ISS. [unreadable] Assuming success in each Specific Aim, this program is intended to produce an IND-ready product that could rapidly move into clinical testing. [unreadable] [unreadable]